Abstract: A central goal in modern neurobiology is to understand the neural mechanisms that convert sensory inputs from the outside world into behavioral outputs that generate specific actions. Functional defects in the neural links that couple sensory inputs to effective behaviors are at the core of many devastating neurological disorders;diseases ranging from anxiety disorder to autism are all ultimately pathological states in which primary sensory inputs are intact but behavioral responses to stimuli are altered. Although we have an increasingly sophisticated view of how genetic and molecular defects in the nervous system lead to functional alterations in individual neurons, we lack a basic understanding of how neural diseases alter circuit function, which ultimately is the cause of disease. Here we propose a series of new technologies to generally probe neural circuit structure and function, including an in vivo method for identifying the molecular receptors for odorants, the development of a viral anterograde neural tracer that allows genetic manipulation of neurons connected in a circuit, and the implementation of a next-generation neural tracing strategy based upon photoconvertible fluorophores. We will use these tools to identify and characterize a model circuit within the mammalian brain responsible for generating odor-driven fear behaviors. In addition to its direct relevance to anxiety and panic disorder, this circuit will serve as an invaluable platform for testing theories about sensory coding, learning and adaptation, and the mechanisms of neural disease. These experiments will lead to important discoveries about the functional architecture of behaviorally-relevant neural circuits that can be generally applied to our understanding of how circuits are disrupted during disease, and will lead to the development of important new tools that can be generally deployed to explore circuits in the mammalian brain. Public Health Relevance: Functional defects in the neural links that couple sensory inputs to effective behaviors are at the core of many devastating neurological disorders;we therefore propose to develop new tools to probe the structure and function of a model neural circuit responsible for generating sensory-driven fear responses in mammals. Understanding this circuit will reveal fundamental principles by which sensation is translated into action, offering a window into how pathological damage to neural circuits alters their function. Because the tools we are developing can be used to study many important neural circuits in the brain, and because the circuit we are dissecting with these tools is relevant to important and prevalent diseases like anxiety and panic disorder, this work will have a broad biomedical and socioeconomic impact.